Stability and Expression Levels of HLA-C on the Cell Membrane Modulate HIV-1 Infectivity

Francesca Parolini, Priscilla Biswas, Michela Serena, Francesca Sironi, Valentina Muraro, Elisabetta Guizzardi, Lucia Cazzoletti, Maria Teresa Scupoli, Davide Gibellini, Elisabetta Ugolotti, Roberto Biassoni, Alberto Beretta, Mauro Malnati, Maria Grazia Romanelli, Donato Zipeto

Research output: Contribution to journalArticlepeer-review

Abstract

HLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes and the triggering of activating killer immunoglobulin-like receptors on NK cells, whereas lower levels may provide poor HIV-1 control and rapid progression to AIDS. We characterized the relative amounts of HLA-C heterotrimers (heavy chain/β2 microglobulin [β2m]/peptide) and HLA-C free heavy chains on peripheral blood mononuclear cells (PBMCs) from healthy blood donors harboring both alleles with stable or unstable binding to β2m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMCs with various allotypes. We observed significant differences in HLA-C heterotrimer stability and in expression levels. We found that R5 HIV-1 virions produced by PBMCs harboring unstable HLA-C alleles were more infectious than those produced by PBMCs carrying the stable variants. We propose that HIV-1 infectivity might depend both on the amounts of HLA-C molecules and on their stability as trimeric complex. According to this model, individuals with low-expression HLA-C alleles and unstable binding to β2m/peptide might have worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication.IMPORTANCE Following HIV-1 infection, some people advance rapidly to AIDS while others have slow disease progression. HLA-C, a molecule involved in immunity, is a key determinant of HIV-1 control. Here we reveal how HLA-C variants contribute to the modulation of viral infectivity. HLA-C is present on the cell surface in two different conformations. The immunologically active conformation is part of a complex that includes β2 microglobulin/peptide; the other conformation is not bound to β2 microglobulin/peptide and can associate with HIV-1, increasing its infectivity. Individuals with HLA-C variants with a predominance of immunologically active conformations would display stronger immunity to HIV-1, reduced viral infectivity and effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from β2 microglobulin/peptide would have a reduced immunological response to HIV-1 and produce more infectious virions. This study provides new information that could be useful in the design of novel vaccine strategies and therapeutic approaches to HIV-1.

Original languageEnglish
JournalJournal of Virology
Volume92
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

Keywords

  • Adult
  • Alleles
  • Antigen Presentation
  • Blood Donors
  • Cell Membrane/genetics
  • Female
  • HIV Infections/immunology
  • HIV-1/pathogenicity
  • HLA-C Antigens/chemistry
  • Histocompatibility Antigens Class I/classification
  • Humans
  • Killer Cells, Natural/immunology
  • Leukocytes, Mononuclear/immunology
  • Male
  • Middle Aged
  • T-Lymphocytes, Cytotoxic/immunology
  • Young Adult
  • beta 2-Microglobulin/genetics

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